Derivatives of the cyclopentanopolyhydrophenanthrene series



Patented Mar. 2, 1943 DERIVATIVES OF THE CYCIDPENTANO POLYHYDROPHENANTHBENE' SERIES Tadeus Reichstein, Basel, Switzerland, assignor. by mesne assignments, to Boche-Ornnon, Inc., Nutley, N. 1., a ccrporationot New Jersey No Drawing. Application January 9.1939, Serial No. 250,025-. In the Netherlands January 13,

13 Claims. (Cl. 260-49'L4) This invention relates to derivatives of the cyclopentano-dimethyl-polyhydro-phenanthrene series having at the carbon atom On a side chain oi the form -CHH.CH2OH, carrying further substituents in the ring system, and more particularly to those compounds of this class as contain a carbonyl group at the carbon atom Ca.

The substances mentioned are valuable as medicines or as intermediates for the production of medicines.

According to the invention the compounds mentioned are prepared from cyclopentano-dimethyl-polyhydro-phenanthrene derivatives having the same side chain but having at the carbon atom C: a hydroxyl group.

Hence it is an object of my invention to sub- Ject these polyhydroxy compounds to an oxidation so that the hydroxyl group at-Ca is converted to a carbonyl group.

However, if the polyhydroxy compounds were oxidized the side chain would also be attacked. This can be prevented by protecting the hydroxyl groups in the side chain against attack by the oxidant. I

Hence it is more particularly the object of my invention to oxidize the polyhydroxy compounds in such a form that the hydroxyls in the side chain are not attacked.

The protection of the hydroxyl groups in the side chain can be effected in different ways.

I have found that the simplest method is to prepare a compound of the acetal type with a carbonyl compound which is possible in this case as the hydroxyl groups in the side chain are attached to adjacent carbon atoms.

These acetal compounds have the side chain in which R1 and Ra-are alkyl radicals or R1=H and R: is an alkyl radical.

This means that aldehydes as well as ketones can be used. Further, aliphatic as well as alicyclic carbonyl compounds can be used, e. g. acetone and cyclohexanone.

' By saponification in an acid solution the hydroxyl groups can be regenerated.

On the other hand it is possible to prepare compounds in which thehydroxyl groups of the side chain are. protected by acylation. -These compounds may be prepared by a series of partial acylations and saponiflcations. One may e. g. start with diacetoxy-3.2l-pregnene-5-one-20 which is carefully reduced so that the carbonyl group at C20 is converted to a hydroxyl group. The product is then esterifled with benzoylchloride to the benzoate-20. This may be partially saponified to set free the hydroxyl groups at C: and C21. Now the hydroxyl group at C21 being a primary hydroxyl group can'be esterified e. g.

with benzoylchloride without esterifying the hydroxyl group. at C3. In this ,way the compounds with a free hydroxyl group at C: and protected hydroxyl groups in the side chain are obtained.

This method of protecting the side chain is, of course, less simple than the first mentioned method.

The oxidation can be carried outwith all oxidants which are known to be suitable for the conversion of a hydroxyl group to a carbonyl group. The method of oxidizing with a carbonyl compound in the presence of an alcoholate of aluminium or magnesium chloride is especially suitable in this case (cf. British Patent Specification No. 487,360)

When the starting materials for the process of this invention have been prepared by reduction of the corresponding compounds with a carbonyl group at C20 the resulting polyhydroxy compound is a mixture of two stereo-isomers. This isomerism is due to the reduction of the carbonyl group.

The two isomers also form two different acetal compounds. It is, however, not necessary to separate the isomers when carrying out the oxidation according to the present inventiomflv A separation may be efiected with the productor the oxidation, e. g. by chromatographic analysis, by fractional crystallisation, etc.

Further substituents in the moleculedo not interfere with the process of this invention. So e. g. a hydroxyl groupat C11, if any, would not enter into the reaction because of its low reactivity as a tertiary hydroxyl group.

If other hydroxyl groups were present in the ring system, e. g. at C11, these could possibly be oxidized to carbonyl groups. This, however, is irrelevant for the purpose of this invention.

EXAMPLE As a starting material pregnene-5-triol-3.20.2l is taken. This may e. g. be prepared from pregnene-5-diol-3.2l-one-20 or its derivatives acylated in the hydroxyl groups at C3 and/or at C21 by careful reduction, e. g. with isopropylalcohol and aluminium-isopropylate, according to Meerwein- Ponndorfl. If acyl derivatives were used the reduction product must further be saponified. In

this way the tree presume-54110142021 can be obtained as 'a mixture-o! two isomers i'orming colourless crystals melting at 204-218.

Thhiormsthestartingmaterialiorthetrestment according to the invention, as follows:

(a) of mono-acetone compound 570 mg. oi trlolweredissolved in 300 cm. or

'dryacetoneandshakeniorlidayswith6g.oi

anhydrous copper sulfate. The copper suli'ate was'thereupon filtered oiinthesolution was shaken with potassium carbonate and evaporated todryness. Thecrystallineresiduewassublb mated in a high vacuum [0.01 mm. and140-160'] A non-distillable residue remained. The sublimate was recrystallized from ether-pentane The yield was 355 mg. of crystals melting at 146' (corn), resolidiiying upon iurther heating and melting again at ltd-169 (corn) [a] 51:8' (c=2.'l37 in acetone).

The compound gives an intense yellow colour with nitro-methane showing the presence 01! a double bond.

(5) Oxidation of mono-acetone compound 375 mg. of the monoacetonepregnenetriol prepared according to (a) were dissolved in 8 cm. of dry acetone and refluxed ior 14 hours with a solution of 0.8 g.. of aluminium tertiary butylate in 30 cm. of benzene. Then the acetone was removed, the solution taken up in ether and washed subsequently with a concentrated sci-- gnette salt solution, sodium carbonate solution and water. The washings were again extracted with ether and added to the bulk 'oi the extract. The united ethereal extracts were then dried and evaporated leaving as a residue 550 mg. oi a slightly yellow oil which was further iractionally distilled in a high vacuum the pressure being 0.005 mm. Hg. At 50' bath temperature a first running came over which was discarded. The bulk of the mass passed at about 170; its weight was 390 mg.

(c) Fractionation of monoacetone-20.21-pregnene-4-one-3-diol-20.2 1

tically no more solids were eluted. Upon evaporation the oxidation product crystallizes. The column was further washed with ether which eluted 50 mg. 01' unchanged starting material.

The ketone fraction was recrystallized from pentane whereby a part wasobtained as pure crystals melting at 124-125.

The lower melting and the syrupy components were now again subjected to a chromotographic asiasea the exception oi petroleum other. In water it is practicallyinsoiuble.

Themotherlieuorsiromthecrystallisationoi the a-iorm and the fraction which was obtained bensene and 0.4 mg. or aluminium tertiary buat) Preparation of 1m pregnene-l-di'ol-Zflliones-3 -Form.235 mg. oi a-mono-acetone compound obtained according to ((9 were dissolved in 8 cm. oi. ethanol and upon addition or 10 cm. oi water and 2.5 cm. 0! glacial acetic acid the solution was refluxed for 2 hours on a water bath. Then it was evaporated to dryness in vacuo whereupon the same treatment ,was twice repeated. The crystalline residue so obtained was extracted iive times with ether which dissolved it almost com-' separation whereupon the several elutrates with 50% benzene-pentane were worked up separately. In all 245 mg. crystals of the a-iorm (M. P. 122-124?) were obtained. After recrystallisation from pentane the melting point rose to 126 The a-mono-acetone pregnene-i-diol 20.21-

one-8 is easily soluble in all organic solvents with pletely. Upon evaporation mg. oi crystals melting at 166-176 (mm) were obtained. =+92.6- :1' (c=1.932. in abs. ethanol). The substance is easily soluble in ethanol and acetone, difllcultly soluble in ether and hardly soluble in petroleum ether.

p-F0rm.-Thls one was prepared from the corresponding acetone compound in exactly the same way as the u-compound. The melting point, however, was 183-185 (corn) The mixed melting point of aand p-iorms was 138-155 (corn).

What I claim is:

1. A process comprising oxidizing compounds or the cyclopentano-dimethyl-po yhydro-phenanthrene series having at Cm a side chain oi the form --CHR1.CH:R:, R1 and Rs standing for radicals which are convertible into a hydroxyl group, and ahydroxyl group at the carbon atom C: to convert the C: hydroxyl group to a keto group.

2. A process comprising oxidizing compounds of the cyclopentano-dimethyl-polyhydro-phenanthrene series having at C11 a side chain 0! the form CHR1.CH:R:, R1 and R: standing i'or radicals which are convertible into a hydroxyl group, and a .hydroxyl group at the carbon atom Cs to convert the 0: hydroxyl group to a keto group and thereupon subjecting the product to a hydrolysis whereby to convert the R1 and Rs groups to Y O YI D 3. Theprocessoi claim 1 inwhichlhandRs are acylonl groups.

4.Theprocessoiclaim2inwhichR1andRs together form a group oi the acetal type.

5. Theprocessotclaim linwhichtheoxidation is eiiected by means 0! dehydroge agents. w

, 6. A process comprising treating pregnene-5- trial-3.20.21 with acetone, oxidizing the acetone The in which the substituents R are selected from the group consisting of hydroxyl groups and radicals which can be converted to hydroxyl groups by hydrolysis.

10. Compounds of the type as defined in claim 9 characterized by the occurrence of a double bond between the carbon'atoms C4 and C5.

11. As new compositions of matter the compounds from the group consisting oi the pregnene-4-one-3-diois-2021 having the general 101'- muia CnHazOa and the structure OBOE-CHICK and their carboxyiic acid esters.

12. z-Pregnene-d-one-ii dio1-20.21 having a 15 melting point 0! 186-176 C. I

13. p-Pregnene-4-one-3-diol-2021 having a melting point of 183-185 C.

'ran'rios REICHS'I'EIN. 

